With the increasing maturity of percutaneous transhepatic cholangioscopy and biliary drainage techniques, PTOBF has gradually emerged as a novel minimally invasive treatment for biliary strictures and hepatolithiasis. This retrospective single‑center study included 25 post‑liver transplant patients diagnosed with biliary strictures and stones between January 2022 and December 2025, aiming to further evaluate the clinical efficacy and safety of PTOBF. The degree of stricture, distribution of stones, total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fibrinogen (FIB), γ-glutamyl transpeptidase (r-GGT), prothrombin time (PT), C-reactive protein(CRP), postoperative complication rate, stricture resolution rate, and stone clearance rate, etc., were analyzed. A total of 73 PTOBF procedures were performed on the 25 patients to manage strictures. The mean bile duct diameter after dilatation was 5.472 ± 0.667 mm. The stricture resolution rate was 92.0% (23/25). During a mean follow-up period of 19.1 ± 8.2 months, the final stone clearance rate was 88.0% (22/25). Compared with preoperative levels, postoperative levels of DBIL, ALT, AST, and FIB were significantly reduced. In this small retrospective cohort, PTOBF was associated with favorable stricture resolution and stone clearance rates, suggesting significant clinical potential. Prospective studies are needed to confirm efficacy and safety.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge due to its late diagnosis and intrinsic treatment resistance, exacerbates by its development from chronic inflammation to cancer transition (ICT). Here, this investigation aims to develop and evaluate ABSi-148, a novel near-infrared (NIR) agent targeting hypoxic carbonic anhydrase IX (CA IX), for its potential applications in ICT imaging and even PDAC treatment. ABSi-148 is synthesized from 4-(2-Aminoethyl) benzene sulfonamide (ABS), a sulfonamide derivative, conjugating with MHI-148 dye with merits of exceptional NIR-emitting traits, high biocompatibility, and deep tissue penetration imaging capability. It selectively accumulates in CoCl2-induced pancreatic stellate cells and pancreatic cancer cells via binding with transmembrane CA IX in vitro. Meanwhile, ABSi-148 effectively visualizes the early pancreatic lesion, and its long-term administration inhibits the progression of hypoxia-related fibrosis involved in pancreatic intraepithelial neoplasias (PanINs), and even PDAC progression in vivo. Besides, ABSi-148 monitors treatment efficacy and localizes hypoxic tumor regions, enhancing survival in tamoxifen combined with caerulein-induced KPC mice. Overall, ABSi-148 emerges as a theranostic NIR agent for precise diagnosis and targeted therapy in ICT of PDAC, promising to alleviate tumor progression and enhancing outcomes.

BackgroundHepatic arterial infusion chemotherapy (HAIC) combined with targeted immunotherapy has emerged as a key therapeutic option for advanced (or unresectable) hepatocellular carcinoma (HCC). Nevertheless, treatment efficacy varies significantly among individuals. Sarcopenia, characterized by loss of muscle mass and strength, may adversely affect therapeutic outcomes and patient prognosis. This study investigates the clinical relevance of sarcopenia in patients undergoing HAIC combined with targeted immunotherapy.MethodsA total of 265 patients with unresectable HCC who received HAIC combined with targeted immunotherapy were retrospectively enrolled in this study and divided into two groups (sarcopenic and non-sarcopenic group). Sarcopenia was defined based on handgrip strength (HGS), with a cutoff value of less than 28kg(male) and 18kg(female). Overall survival (OS) and progression-free survival (PFS) were compared between groups using the log-rank test and multivariate Cox proportional hazards models. Additionally, propensity score matching (PSM) was applied to minimize baseline differences and enhance comparability. Then, differences in treatment response, survival outcomes, and adverse events between the sarcopenic and non-sarcopenic groups were evaluated using appropriate statistical analyses.ResultsPatients in sarcopenia group exhibited significantly poorer OS and PFS compared to those with non-sarcopenic group. Sarcopenia was also associated with lower objective response rates. Multivariate analysis confirmed that sarcopenia was an independent prognostic factor for poor outcomes.ConclusionSarcopenia is a significant predictor of poor prognosis in patients with unresectable HCC treated with HAIC combined with targeted immunotherapy. Incorporating HGS assessment into clinical practice may help optimize individualized treatment strategies and enhance patient management.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis.

BACKGROUND Biliary stone disease is a highly prevalent condition and a leading cause of hospitalization worldwide. Hepatolithiasis with associated strictures has high residual and recurrence rates after traditional multisession percutaneous transhepatic cholangioscopic lithotripsy (PTCSL). AIM To study one-step PTCSL using the percutaneous transhepatic one-step biliary fistulation (PTOBF) technique guided by three-dimensional (3D) visualization. METHODS This was a retrospective, single-center study analyzing, 140 patients who, between October 2016 and October 2023, underwent one-step PTCSL for hepatolithiasis. The patients were divided into two groups: The 3D-PTOBF group and the PTOBF group. Stone clearance on choledochoscopy, complications, and long-term clearance and recurrence rates were assessed. RESULTS Age, total bilirubin, direct bilirubin, Child-Pugh class, and stone location were similar between the 2 groups, but there was a significant difference in bile duct strictures, with biliary strictures more common in the 3D-PTOBF group (P = 0.001). The median follow-up time was 55.0 (55.0, 512.0) days. The immediate stone clearance ratio (88.6% vs 27.1%, P = 0.000) and stricture resolution ratio (97.1% vs 78.6%, P = 0.001) in the 3D-PTOBF group were significantly greater than those in the PTOBF group. Postoperative complication (8.6% vs 41.4%, P = 0.000) and stone recurrence rates (7.1% vs 38.6%, P = 0.000) were significantly lower in the 3D-PTOBF group. CONCLUSION Three-dimensional visualization helps make one-step PTCSL a safe, effective, and promising treatment for patients with complicated primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for patients with complicated primary hepatolithiasis. This minimally invasive method has the potential to be used as a substitute for hepatobiliary surgery.

Aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. Methods: The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. Results: High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. Conclusion: Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.

BackgroundEchovirus type 11(E-11) can cause fatal haemorrhage-hepatitis syndrome in neonates. This study aims to investigate clinical risk factors and early markers of E-11 associated neonatal haemorrhage-hepatitis syndrome.MethodsThis is a multicentre retrospective cohort study of 105 neonates with E-11 infection in China. Patients with haemorrhage-hepatitis syndrome (the severe group) were compared with those with mild disease. Clinical risk factors and early markers of haemorrhage-hepatitis syndrome were analysed. In addition, cytokine analysis were performed in selective patients to explore the immune responses.ResultsIn addition to prematurity, low birth weight, premature rupture of fetal membrane, total parenteral nutrition (PN) (OR, 28.7; 95% CI, 2.8–295.1) and partial PN (OR, 12.9; 95% CI, 2.2–77.5) prior to the onset of disease were identified as risk factors of developing haemorrhage-hepatitis syndrome. Progressive decrease in haemoglobin levels (per 10 g/L; OR, 1.5; 95% CI, 1.1–2.0) and platelet (PLT) < 140 × 10⁹/L at early stage of illness (OR, 17.7; 95% CI, 1.4–221.5) were associated with the development of haemorrhage-hepatitis syndrome. Immunological workup revealed significantly increased interferon-inducible protein-10(IP-10) (P < 0.0005) but decreased IFN-α (P < 0.05) in peripheral blood in severe patients compared with the mild cases.ConclusionsPN may potentiate the development of E-11 associated haemorrhage-hepatitis syndrome. Early onset of thrombocytopenia and decreased haemoglobin could be helpful in early identification of neonates with the disease. The low level of IFN-α and elevated expression of IP-10 may promote the progression of haemorrhage-hepatitis syndrome.

Background: Epithelial–mesenchymal transition (EMT) plays a critical role in the recurrence and metastasis of hepatocellular carcinoma (HCC). Some long noncoding (lnc)RNAs are involved in this process through the regulation of EMT-related transcription factors. Methods: In this study, we established a novel EMT-related lncRNA signature in HCC and identified hub lncRNAs that can serve as potential therapeutic targets. Differentially expressed lncRNAs were identified by screening HCC patient data from The Cancer Genome Atlas, and a correlation analysis was performed to identify those associated with EMT. The EMT-related lncRNA signature was established by univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. After verifying the prognostic accuracy of the signature, its relationships to immune cell infiltration and immune checkpoint targets were explored. LINC01116 was identified as a hub lncRNA and its role in HCC was investigated in vitro and in vivo. Results: A 5-lncRNA signature was developed for HCC and its prognostic accuracy was assessed by survival, time-dependent receiver operating characteristic curve, clinical correlation, and Cox regression analyses. The correlation analysis showed that the lncRNA signature was closely related to immune cell infiltration and 10 immune checkpoint targets and also predicted the prognosis of HCC patients with high accuracy. In vitro and in vivo experiments revealed that LINC01116 stimulated cell proliferation, cell cycle progression, and tumor metastasis. We also found that LINC01116 was closely related to immune regulation. Conclusions: These results demonstrate that LINC01116 is an immune-related oncogene that is associated with both EMT and immune regulation in HCC. Moreover, the EMT-related lncRNA signature that includes LINC01116 can guide risk stratification and clinical decision-making in HCC management.

Introduction: Philadelphia chromosome (Ph) positive myelodysplastic syndrome (MDS) is a very rare disease. At present, the specific role of Ph in MDS is not clear, but such patients seem to have a poor prognosis, so the disease deserves attention. Here, we describe the history of a woman with Ph-positive MDS and perform a systematic review of related literature. Patient concerns and diagnosis: We report a 38-year-old woman with Ph-positive MDS. Interventions and outcomes: She received chemotherapy with decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (DCAG) combined with imatinib mesylate and achieved a bone marrow remission. She then underwent an allogeneic hematopoietic stem cell transplant. The condition is good and no recurrence of the disease has been observed. Conclusion: Ph-positive MDS is a very rare disease. Ph may aid in the malignant progression of MDS leaving such patients with a very poor prognosis. Tyrosine kinase inhibitors (TKIs) plus chemotherapy followed by allogeneic hematopoietic stem cell transplantation has provided these patients with satisfactory outcomes.

Background: Endoscopic management is the mainstay for biliary strictures after liver transplantation. However, this method is often failed in cases associated with hepatolithiasis or refractory strictures. The aim of this study is to investigate whether 1-step percutaneous transhepatic biliary cholangiography (PTC) combined with high-frequency needle-knife electrotomy can be an alternative method in biliary strictures after liver transplantation that could not be treated by endoscopic management. Methods: Clinical data of 14 patients suffering from biliary strictures after liver transplantation from June 2014 to January 2018 were retrospectively analyzed. One-step PTC combined with high-frequency needle-knife electrotomy was used to resolve the strictures. Results: One-step PTC was successfully performed in all 14 patients. In 10 of 12 (83.3%) patients with hepatolithiasis, the stones were removed completely. Stricture resolution was detected in 13 of 14 (92.9%) patients at first postoperative choledochoscopy. Three mild adverse events occurred (cholangitis, 2 patients; delayed hemobilia, 1 patient), but were resolved with conservative treatment. The follow-up after supporting catheter removal was 15.7±4.5 months. Only 1 patient (8.3%) had stone recurrence and no stenosis occurred during supporting-catheter-free follow-up. Conclusions: One-step PTC combined with high-frequency needle-knife electrotomy seems to be a useful for treating biliary strictures after liver transplantation.

BACKGROUND:Endoscopic retrograde cholangiopancreatography (ERCP) may be inappropriate for most patients with choledocholithiasis. This study aimed to evaluate one-step percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) in the treatment of patients with choledocholithiasis who could not undergo ERCP (e.g., failed ERCP, altered anatomy, and/or contra-indications).METHOD:This was a retrospective single-centre series of 67 patients who underwent choledocholithiasis between November 2015 and March 2018: 35 with one-step PTCSL (Group A) and 32 with laparoscopic common bile duct (CBD) exploration (Group B).RESULTS:Compared with Group B, Group A showed shorter duration of operation, length of stay in the hospital, postoperative hospital stay, postoperative drainage time, and time to oral intake (all P<0.05). Intraoperative blood loss, costs, conversion to open surgery (one in group A vs. seven in group B; P=0.023), and bile leakage (none in group A vs. four in group B; P=0.047) were lower in Group A than in Group B. There were no significant differences between the two groups regarding the intraoperative clearance rate, ultimate clearance rate, and several postoperative complications.CONCLUSION:One-step PTCSL could be an alternative for patients with choledocholithiasis, especially when ERCP is not feasible.

Abstract Background: Biliary atresia (BA) is a severe cholangiopathy resulting from virus-induced and immune-mediated injury of the biliary system. IFN-g, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death 1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver. Blockade of PD-1 increased IFN-g expression in CD4+ T and CD8+ T cells, suppressed bilirubin production and exacerbated liver immunopathology.Conclusions: PD-1 plays a protective role in infants with BA by suppressing IFN-g production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

Abstract Background Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = − 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = − 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 μmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. Conclusions PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

ABSTRACTRespiratory disease caused by the 2019 novel coronavirus (2019-nCoV) pneumonia first emerged in Wuhan, Hubei Province, China, in December 2019 and spread rapidly to other provinces and other countries. Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV and has been suggested to be also the receptor for 2019-nCoV. Paradoxically, ACE2 expression in the lung protects mice from SARS-CoV spike protein induced lung injury by attenuating the renin-angiotensin system. In the intestine, ACE2 also suppresses intestinal inflammation by maintaining amino acid homeostasis, antimicrobial peptide expression and ecology of the gut microbiome. Upon analysis of single cell-RNA sequencing data from control subjects and those with colitis or inflammatory bowel disease (IBD), we found thatACE2expression in the colonocytes was positively associated with genes regulating viral infection, innate and cellular immunity, but was negatively associated with viral transcription, protein translation, humoral immunity, phagocytosis and complement activation. In summary, we suggest that ACE2 may play dual roles in mediating the susceptibility and immunity of 2019-nCoV infection.

The aim of this study was to compare the outcomes of one-step multichannel percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) with traditional PTCSL in the treatment of bilateral hepatolithiasis. From February 2011 to June 2015, 156 patients with bilateral hepatolithiasis received surgical treatment in our department. Among these patients, 81 received one-step multichannel PTCSL (group A), and the remaining 75 received traditional PTCSL (group B). Compared with group B, group A was characterized by a significantly shorter operation time (83.7 ± 28.5 min vs 118.1 ± 41.5 min; P = 0.000), hospital stay (11.1 ± 3.4 d vs 17.8 ± 5.6 d; P = 0.034), and postoperative hospital stay (6.9 ± 3.1 d vs 9.6 ± 4.5 d; P = 0.026). In addition, the immediate clearance (62.9% vs 45.3%, P = 0.027) and final clearance (90.1% vs 78.7%, P = 0.048) rates were higher in group A than in group B. During the follow-up period, stone recurrence was significantly less common in group A than in group B (13.6% vs 26.7%, P = 0.041). Multivariate Cox analysis showed that the PTCSL method (HR = 2.32, 95% confidence interval [CI] = 1.09–4.90, P = 0.028), bilateral biliary stricture (HR = 4.17, 95% CI = 1.73–10.03, P = 0.001), and stones located in segments I (HR = 7.75, 95% CI = 3.67–16.38, P = 0.000) were independent predictors of recurrence. Compared with traditional PTCSL, one-step multichannel PTCSL was more efficient and effective in the treatment of bilateral hepatolithiasis.

Objective To study the efficacy and safety of percutaneous transhepatic one-step biliary fistulation (PTOBF) with rigid cholangioscopic lithotripsy for treatment of complicated hepatolithiasis under the ultrasonic navigation technique.Methods In this retrospective study,PTOBF lithotripsy surgery was performed in 94 patients with hepatolithiasis under general anesthesia with tracheal intubation,and with percutaneous transhepatic puncture of targeted bile duct under ultrasonic navigation in The First Affiliated Hospital of Guangzhou Medical University.Biliary expanders were used along a guidewire to expand the sinus gradually until 14Fr to establish a fistulous channel.Lithotripsy was then performed through the channel by rigid cholangioscopy.The operation-related data were collected and analyzed,including puncture and fistula establishment success ratio,complication rate,intraoperative blood loss,residual and recurrence hepatolithiasis rates.Results 94 patients (total 122 patient-times) underwent PTOBF lithotripsy.There was no perioperative mortality.The overall puncture success rate was 100％,and the fistula/puncture rate was 97.5％ (119/122).In 118 patients success was achieved in 2 time (96.7％).The complication rate was 9.6％ (9/94).The average intraoperation blood loss were (24.9 ± 21.3)ml.The residual calculus rate after therapy was 13.8％ (13/94).All patients were followed-up for a period that ranged between 18 and 30 months.The recurrence rate was 14.9％ (14/94).Conclusions Ultrasonic navigation technique plays an important role in bile duct puncture,sinus expansion and rigid cholangioscopic lithotripsy for treatment of complicated hepatolithiasis.PTOBF lithotripsy is a safe and effective procedure,which provides a new way in mini-invasive treatment for hepatolithiasis.It is worth generalizing.

Objective To observe the clinical effect of percutaneous transhepatic one-step biliary fistulation (PTOBF) and percutaneous transhepatic cholangioscopy (PTCS) in the treatment of hepatolithiasis with hepatobiliary surgery history,and to explore the clinical application value of PTOBF.Methods This is retrospective analysis of 68 patients with hepatolithiasis who were admitted to hepatobiliary surgery in the First Affiliated Hospital of Guangzhou Medical University from November 2009 to October 2017.Among these cases,35 patients in the observation group (group PTOBF) were treated with PTOBF,and 33 patients in the control group (group PTCS) received PTCS treatment.The final clearance rate,the postoperative complications rate,the hospitalization time,the operation times within the course of treatment,the recurrence rate and the residual stenosis rate of the two groups were compared.Results Compared with group PTCS,the clearance rate was significantly higher in group PTOBF(82.9％ vs 54.6％,P＜0.05),while the postoperative complications rate between the two groups are similar (14.3 ％ vs 30.3 ％,P＞ 0.05);Besides,the hospitalization time(12.3±5.3 d vs 17.4±7.0 d,P＜0.05),the operation times within the course of treatment (2.2±1.3 vs 2.8±1.0,P＜0.05) and the recurrence rate(17.4％ vs 39.4％,P＜0.05) of group PTOBF were obviously lower.Conclusions PTOBF is a safe and feasible treatment for hepatolithiasis with hepatobiliary surgery history.Compared with PTCS,it has the advantages of short hospitalization time,fewer operations and better recovery.

INPP4B has been recently shown to be a poor prognostic marker and confer chemo- or radio-resistance in AML cells, whereas, the underlying mechanisms remain unclear. Herein, we aimed to explore the possible mechanisms mediated the resistance to chemotherapy in AML. We found that INPP4B-mediated resistance to genotoxic drug, cytarabine, was accompanied by lower p-H2AX accumulation in KG-1 cells, and INPP4B knockdown evidently sensitized KG-1 cells to cytarabine, meanwhile, p-H2AX expression was increased dramatically. Then, we observed that INPP4B knockdown inhibited the loss of p-H2AX expression after cytarabine removal in INPP4B-silenced KG-1 cells, whereas, in control KG-1 cells, the expression of p-H2AX was reduced in a time-dependent manner. Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51. Furthermore, nuclear localization of p65 was inhibited after INPP4B knockdown, and reactivation of p65 can rescue the INPP4B knockdown-induced inhibition of ATM, p-ATM, p-BRCA1, p-ATR, and p-RAD51. Finally, INPP4B expression was positively correlated with ATM expression in AML cells, both INPP4B knockdown and KU55933 can significantly sensitize primary myeloid leukemic cells to cytarabine treatment.Collectively, these data suggest that enhanced ATM-dependent DNA repair is involved in resistance to chemotherapy in INPP4Bhigh AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4Bhigh AML.

Primary hepatolithiasis is a common bile duct disease with benign nature but complicated mechanisms. Current studies have revealed its correlation with cytokine release by chronic inflammation, which also increased mucin (MUC) synthesis. This study investigated the role of p38 mitogen-activated protein kinase (MAPK) in regulating cytokine release and mucin synthesis, in an attempt to elucidate the role of p38 signaling molecule in the pathogenesis of hepatolithiasis. In human intrahepatic bile duct endothelial cells (HIBECs), lipoprotein (LPS) was used to induce the high expression of MUC. Small interference RNA (siRNA) was then used to silencing p38 gene expression. Cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured, along with MUC5AC protein and mRNA expression assay. The interference of p38 gene expression inhibited the release of IL-1β and TNF-α in cultured cells. It also depressed both mRNA and protein levels of MUC5A. P38 MAPK signal pathway may be involved in the formation and progression of hepatolithiasis. This study provides potential new strategy for treating hepatolithiasis using p38 MAPK signal pathway as the drug target.